rs3803231

Variant names:

• chr13-110466995-T-C
• rs3803231
• NM_001846.4:c.2039-45T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.2039-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,612,008 control chromosomes in the GnomAD database, including 8,902 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (878 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8024 hom.)
• Consequence: COL4A2 NM_001846.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.64
• Publications: 7 publications found

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-110466995-T-C is Benign according to our data. Variant chr13-110466995-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.2039-45T>C		intron_variant	Intron 26 of 47	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.2039-45T>C		intron_variant	Intron 26 of 47	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15851 AN: 151958 Hom.: 876 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.108 AC: 26706 AN: 248124 AF XY: 0.108

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.103 AC: 150543 AN: 1459932 Hom.: 8024 Cov.: 31 AF XY: 0.103 AC XY: 75049 AN XY: 726254

African (AFR) AF: 0.105 AC: 3522 AN: 33428

American (AMR) AF: 0.118 AC: 5259 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3735 AN: 26040

East Asian (EAS) AF: 0.0838 AC: 3321 AN: 39626

South Asian (SAS) AF: 0.108 AC: 9297 AN: 86122

European-Finnish (FIN) AF: 0.0730 AC: 3891 AN: 53312

Middle Eastern (MID) AF: 0.160 AC: 921 AN: 5762

European-Non Finnish (NFE) AF: 0.103 AC: 113957 AN: 1110762

Other (OTH) AF: 0.110 AC: 6640 AN: 60294

GnomAD4 genome AF: 0.104 AC: 15864 AN: 152076 Hom.: 878 Cov.: 32 AF XY: 0.103 AC XY: 7676 AN XY: 74350

African (AFR) AF: 0.102 AC: 4249 AN: 41466

American (AMR) AF: 0.109 AC: 1673 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3466

East Asian (EAS) AF: 0.109 AC: 563 AN: 5172

South Asian (SAS) AF: 0.100 AC: 484 AN: 4824

European-Finnish (FIN) AF: 0.0774 AC: 820 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7203 AN: 67958

Other (OTH) AF: 0.121 AC: 255 AN: 2102

Alfa AF: 0.111 Hom.: 1858

Bravo AF: 0.110

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.032
DANN	Benign	0.26
PhyloP100		-1.6
PromoterAI		0.0076	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3803231; hg19: chr13-111119342;